Sunday, September 13, 2015

By
definition, a molecule is considered aromatic when in its constitution there is
at least one derivative of benzene, ie, a cyclic structure with 6 vertices (all
carbon atoms!), and 3 double bonds (in fact, as I said in other posts, they are
not 3 double bonds, but 6 partially double bonds, with bond order of 1.5).
Therefore, when, in a molecule, there is at least one such structure, the
molecule is considered aromatic.

Probably
some of you may be questioning yourself why to use the concept of
"aromatic". In fact, most of the substances we know that have flavour
(e.g., cinnamon or clove), have their aroma exactly due to the presence of
molecules containing aromatic rings, in this particular case, cinnamaldehyde
and eugenol, respectively. It is the delocalized electron cloud of the derivatives
of benzene rings that give the fragrance to these (and many other!) molecules,
and hence the chemical definition of aromatic is clearly related to the
"physiological" setting of aromatic.

Let us
return to amino... there are 3 that contain a derivative of the benzene ring on
its side chain and are, therefore, referred to as aromatic amino acids:

Phenylalanine - the name itself explains the composition of
this amino acid. In a previous post I talked about the nonpolar amino acids
with aliphatic side chains, among whom was alanine
(this post).
Phenylalanine is no more than an alanine with a phenyl group, ie with a benzene
ring. Since it only has carbon and hydrogen in its side chain, it is a nonpolar
chain.

Tyrosine - this aminoacid is a hydroxylated
phenylalanine. In fact, it only differs from phenylalanine because it presents
a hydroxyl group on the aromatic ring, more precisely on a diametrically
opposed carbon to the alpha carbon position. This hydroxyl group gives it some
polarity, with the resulting side chain being therefore amphipathic.

Tryptophan – it is the amino acid with the more complex side
chain comprising two cyclic structures: one is a benzene derivative, another is
a heterocycle (ring composed of 2 different atoms, carbon and nitrogen in this
case). These two fused rings form a functional group called indol group, which
is amphipathic, since the nitrogen confers some polarity. Tryptophan is very
important from a biological standpoint, because in addition to being used in
the production of proteins, it is also the precursor of many important
molecules, such as, for example, serotonin.

The
tyrosine and tryptophan have an important characteristic, which is that of
absorbing ultraviolet radiation. Due to this, the proteins having these amino
acids (almost all!) present the ability to absorb UV light. In fact,
phenylalanine also absorbs UV radiation, but in much smaller amount than the
other aromatic amino acids, because the chemical modifications of the benzene ring
(hydroxyl group in the case of tyrosine, and embedding the indole group in the
case of tryptophan) significantly increase the UV absorptive capacity of
aromatic rings.

Wednesday, August 19, 2015

As I
mentioned here on the blog, in an earlier post
(this post),
the standard amino acids differ in the chemical composition of their side
chains. The
20 standard amino acids can be divided in 5 groups, according to the
physico-chemical properties of the side chain, in particular, according to
their polarity. Before
starting to talk about this division, I want to mention that it is a division
that involves some ambiguities, which I will highlight as they appear in the
posts that I will devote to this matter.I'll
start by talking about the amino acids with nonpolar aliphatic side chain. First
of all, it should be explained what does it means nonpolar and aliphatic. Nonpolar
means that there are no significant asymmetries in the distribution of
electrons on atoms. Stated
more simply, if a molecule (or a side chain) it is non-polar, it contains atoms
with similar electronegativities. As
mentioned in a previous post
(this post), if a
molecule is composed only of carbon and hydrogen, it is considered non-polar. Similarly,
if a side chain of an amino acid is composed only of carbon and hydrogen atoms,
it is considered to be nonpolar. Regarding
the term "aliphatic", this relates to the absence of aromatic rings,
which are benzene ring derivatives; therefore
they are cyclic structures with six vertices, all of them corresponding to carbon
atoms and 3 double bonds therein (in fact they are not three double bonds, instead
they are six bonds with the connection order of 1.5, but this would complicate things and may be considered
three double bonds). Therefore,
all amino acids having in its side chain only carbon and hydrogen atoms and
that show no aromatic rings, belong to the class of amino acids with nonpolar aliphatic
side chains.

They
are:

Glycine – it is the simplest amino acid with a side chain consisting only of
hydrogen. As
the hydrogen is too small to have a major role in the interaction with other
amino acid side chains, and do not have by itself a polar (or nonpolar)
significant behavior, this amino acid appears in this category by deleting
parts, namely because in
the other categories did not make sense to include it. Glycine
has the distinction of being the only standard amino acid that does not have
stereoisomers because its a carbon is not chiral because it is not
connected to four different substituents.

Alanine – its side chain is a methyl group (-CH3), which fits perfectly in the definition
of nonpolar aliphatic side chain.

Valine, leucine and isoleucine - their side chains are more complex than that
of alanine, but they are composed exclusively of carbon and hydrogen atoms.

Methionine – another amino acid that appears in this group somewhat by a
process of elimination. The
sulfur atom is an inner position of the chain (is a thioether group), and does
not significantly affect the polarity thereof.

All
amino acids in this group will tend to establish London dispersion forces
(so-called "hydrophobic interactions") with neighboring amino acids
and, therefore, in a 3D structure of a protein, they tend to appear in
proximity to each other.

Sunday, July 5, 2015

As
mentioned in one of my last posts, cytochrome c is a small protein, essential
for mitochondrial respiratory chain, where it acts as an electron carrier
between the complex III and complex IV. Besides this very important function,
cytochrome c is also an important activator of programmed cell death, or
apoptosis; more specifically, it is an activator of the intrinsic pathway of
apoptosis. Because of this dual role, cytochrome c is often classified as
"a central molecule for life in our oxygen world, and simultaneously a key
that opens the door to death."

While
apoptosis is a form of cell death, it is a fundamental mechanism for keeping
the homeostasis of our body. In fact, when a cell accumulates irreparable
damage (in DNA or in another biomolecule), when placed in an environment where
it may be potentially dangerous to the remaining cells (shortage of nutrients,
detachment from the surrounding cells, deprivation of growth factors,
infection, autoreactive leukocytes, etc.), or when it is not important in the
body (natural selection of neurons, for example) tends to commit suicide -
apoptosis. This obvious idea, but at the same time strange, suggests something
that I often refer in my classes, that is the fact that multicellular organisms
must be regarded not as a living being composed of many cells, but as a living
community, where each cell has its role, and lives in community with the others.

Apoptosis
is a complex process that involves many mediators and that ultimately leads to
the activation of enzymes that promote cell self-digestion. Caspases are a
class of proteases that plays a key role in the apoptotic response. Overall,
there are defined two apoptosis activation mechanisms: the intrinsic pathway
and the extrinsic pathway. The intrinsic pathway is also sometimes referred to
as pathway initiated by the cytochrome c, since this protein is the main actor
in early apoptotic response. Several stimuli can lead to the release of
cytochrome c from the intermembrane space into the cytosol. When this happens,
it starts the activation of caspases. Under normal conditions cytochrome c does
not abandon the intermembrane space, since it interacts with an existing
glycerophospholipid in the inner mitochondrial membrane, cardiolipin. The high
density of negative charges of the phospholipid electrostatically attracts the
positively charged cytochrome c. In addition, a hydrophobic tail of the lipid is
inserted in a hydrophobic cavity of the protein, enhancing the interaction
between both molecules. It is the damage caused on cardiolipin which can make
these interactions to be destroyed and the cytochrome c released.

Once
in the cytosol, cytochrome c promotes the release of calcium stored in the
endoplasmic reticulum, increasing the ion concentration in the cytosol. One of
the functions of calcium is the stimulation of the release of more cytochrome c
into the cytosol, thus causing a positive feedback loop. A further consequence
of the presence of cytochrome c in the cytosol is the activation of caspase 9,
which in turn activates caspases 3 and 7, and the fate of the cell is irreversible
- death by apoptosis!

Monday, June 22, 2015

The
cytochrome c is a small protein with 104 amino acids and a mass of about 12 kDa
(12.233 kDa in humans). As
a consequence of its small size, it is highly conserved among different
mammalian species; for
example, the human cytochrome c is identical to the chimpanzee! It
is a heteroprotein because beyond its amino acid, it contains also an heme group
as a cofactor, which is bound to cysteines 14 and 17. It is a hydrophilic
protein, highly soluble (solubility ~100 g/L), which is located in the mitochondrial
intermembrane space, where it plays a key role in the mitochondrial respiratory
chain, though it does not belong to any of the four complexes.The
function of the cytochrome c is to receive electrons from the complex III, and deliver
them to the complex IV.

To
acomplish this function, its heme group, as any heme group, has an iron ion
that can oscillate between two different oxidation states (Fe2+ and
Fe3+). Since
it has only 1 heme group, it can carry only one electron at a time. This
feature has two very important consequences:

1.
To deliver the 2 electrons from NADH or FADH2 to O2 in
cellular respiration, it is required 2 molecules of cytochrome c.2.
O2, which is the final electron acceptor of the complex IV, receives one
electron at a time, which means that it converted to, even temporarily (in most
situations!), a free radical, which potentiates the oxidative stress.Other
functions less characterized of citocromoc are its involvement in catalytic
hydroxylation reactions, aromatic oxidation and peroxidation. Also,
it appears to be important to the catalytic activity of the nitrite reductase
enzyme.

Finally,
a very important characteristic of cytochrome c is that it can function as an
activator of the intrinsic pathway of programmed cell death, a process referred
to as apotose. Soon I will
post more information on this subject...